Blood Endocannabinoid Levels Tracked With Anxiety Severity and Treatment Response in Youth
In nearly 200 youth, higher anandamide and lower 2-AG blood levels were associated with more severe anxiety, while increases in 2-AG during SSRI treatment predicted better treatment response.
Quick Facts
What This Study Found
After adjusting for BMI, age, sex, and time of day, higher AEA and lower 2-AG were associated with more severe anxiety symptoms. In a subsample of 41 adolescents with GAD in an 8-week RCT of escitalopram, greater increases in 2-AG from baseline were linked to improved treatment response, without changes in AEA.
Key Numbers
N = 199 youth (ages 9-17). RCT subsample: N = 41 (ages 12-17), escitalopram 15-20 mg/day for 8 weeks. BMI positively correlated with AEA. 2-AG negatively associated with age, female sex, and time of day. Higher AEA and lower 2-AG associated with greater anxiety severity.
How They Did This
Circulating AEA and 2-AG were measured in 199 youth aged 9-17 with varying anxiety levels. Anxiety was assessed using the SCARED questionnaire. A subset of 41 adolescents (12-17) with GAD participated in an 8-week randomized placebo-controlled trial of escitalopram, with endocannabinoid levels measured at baseline and during treatment.
Why This Research Matters
If blood endocannabinoid levels can predict who will respond to anxiety treatment, they could become the first objective biomarkers for guiding psychiatric care in youth. The selective association of 2-AG (but not AEA) with treatment response suggests these two endocannabinoids play different roles.
The Bigger Picture
The endocannabinoid system is emerging as a key regulator of anxiety across the lifespan. This study bridges basic neuroscience and clinical psychiatry by showing that the same endocannabinoid changes seen in animal anxiety models are measurable in the blood of anxious youth and respond to treatment.
What This Study Doesn't Tell Us
Circulating endocannabinoid levels may not perfectly reflect brain levels. The RCT subsample is small (41 participants). Cross-sectional anxiety-endocannabinoid associations cannot determine causation. SCARED is a self-report measure.
Questions This Raises
- ?Could baseline 2-AG levels predict which anxious youth will respond to SSRIs before treatment begins?
- ?Do cannabis-using youth have altered endocannabinoid profiles that affect anxiety treatment?
Trust & Context
- Key Stat:
- 2-AG increases during SSRI treatment predicted better anxiety response
- Evidence Grade:
- Novel biomarker study combining observational data (N=199) with a subsample from an 8-week RCT (N=41). Moderate evidence given the small trial subsample.
- Study Age:
- Published in 2025 in Neuropsychopharmacology.
- Original Title:
- Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors.
- Published In:
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(10), 1606-1614 (2025)
- Authors:
- Marusak, Hilary A(6), Zundel, Clara G(3), Shakir, Tehmina, Ely, Samantha L, Carpenter, Carmen, Shampine, MacKenna, Tamimi, Reem, Matsko, Mariya, Rogers, Sarah, Losiowski, Jennifer, O'Mara, Emilie, Jaster, Alaina M, Sharma, Kamakashi, deRoon-Cassini, Terri A, Hillard, Cecilia J, Schroeder, Heidi K, Mills, Jeffrey A, Strawn, Jeffrey R, Barcelona, Jeanne
- Database ID:
- RTHC-07070
Evidence Hierarchy
Watches what happens naturally without intervening.
What do these levels mean? →Frequently Asked Questions
What are AEA and 2-AG?
Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the two main endocannabinoids naturally produced by the body. They activate the same receptors that THC does and play key roles in mood, anxiety, and stress regulation.
Could this lead to a blood test for anxiety?
Possibly. If replicated in larger studies, endocannabinoid blood levels could help clinicians predict treatment response and tailor anxiety treatment for individual patients.
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Cite This Study
https://rethinkthc.com/research/RTHC-07070APA
Marusak, Hilary A; Zundel, Clara G; Shakir, Tehmina; Ely, Samantha L; Carpenter, Carmen; Shampine, MacKenna; Tamimi, Reem; Matsko, Mariya; Rogers, Sarah; Losiowski, Jennifer; O'Mara, Emilie; Jaster, Alaina M; Sharma, Kamakashi; deRoon-Cassini, Terri A; Hillard, Cecilia J; Schroeder, Heidi K; Mills, Jeffrey A; Strawn, Jeffrey R; Barcelona, Jeanne. (2025). Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(10), 1606-1614. https://doi.org/10.1038/s41386-025-02155-7
MLA
Marusak, Hilary A, et al. "Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors.." Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2025. https://doi.org/10.1038/s41386-025-02155-7
RethinkTHC
RethinkTHC Research Database. "Circulating endocannabinoids in children and adolescents: as..." RTHC-07070. Retrieved from https://rethinkthc.com/research/marusak-2025-circulating-endocannabinoids-in-children
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.